Highlights from Recent Cancer Literature
Journal: Cancer Research (2013)

Hayes CS, Shicora AC, Keough MP, Snook AE, Burns MR, Gilmour SK. Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol Res; Published OnlineFirst October 7, 2013; doi:10.1158/2326-6066.CIR-13-0120-T.Polyamines contribute to malignant progression in a wide array of cancers and are known to drive proliferation, angiogenesis, and immune evasion. Blocking polyamines in cancer requires limiting both cellular uptake and de novo synthesis, the latter achievable using difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis. To explore AMXT1501, an experimental agent that blocks polyamine transport into cells, Hayes and colleagues (senior author SK Gilmour is advisor to the company that makes AMXT1501) tested DFMO and AMXT1501 in combination, using immune-competent allograft mouse models for cancer, in the context of inducible transgenic expression of ornithine decarboxylase. These studies demonstrate that (i) elevated polyamine-mediated suppression of immunity promoted a microenvironment permissive for tumor growth; (ii) inhibition of tumor growth by polyamine depletion was T-cell dependent; and (iii) polyamine depletion before surgical removal of the primary tumor were protective against recurrence. These data suggest a translatable approach to targeting polyamine-dependent immunosuppression in cancer.Schroeder A, Herrmann A, Cherryholmes G, Kowolik C, Buettner R, Pal S, et al. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res; Published OnlineFirst October 31, 2013; doi:10.1158/0008-5472.CAN-13-0594.Prostate cancer is the leading cause of cancer-related death among men. Androgen receptor (AR) signaling is known to enhance the progression of prostate cancer. Current therapeutic interventions aim to block AR signaling and involve androgen deprivation and/or AR targeting-based therapies. However, the use of AR-targeted therapies in prostate cancer treatment is limited because tumor cells that survive therapy recur after therapy as drug-resistant and highly metastatic tumors. Might therapy select for cancer stem-like cells that survive therapy? With this study, Schroeder and colleagues show that loss of AR expression in prostate cancer cells causes activation of STAT3 and development of cancer stem-like cells in vitro. A similar association was observed in human prostate tumor tissues, where tumors with low AR expression showed high STAT3 activity and increased expression of cancer stem-like cell markers. The authors further show that STAT3 activation following AR downregulation was mediated by increased expression of IL-6. Silencing STAT3 in tumor cells or treatment with soluble IL-6 receptor fusion protein, which functions as a cytokine “trap,” resulted in decreased tumor growth and cancer stem-like cells in vivo. These findings support the argument that AR and STAT3 play opposing roles in prostate cancer stem-like cell development and provide novel mechanistic insight into the emergence of drug-resistant prostate cancer. Finally, combining soluble IL-6 receptor fusion protein with AR-targeted therapy might be useful to aid in prevention of tumor relapse.Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci U S A 2013;110:17380–5.The intercellular exchange of biologically active signaling proteins, lipids, and nucleic acids via extracellular vesicles (EV) is thought to contribute to tumor progression. Thus, inhibition of EV formation, packaging, or uptake could have therapeutic utility. Christianson and colleagues identify heparan sulfate proteoglycans (HSPG) as internalizing receptors for cancer cell-derived EVs. Although “EV” refers to a heterogeneous group of membrane-bound structures, including microvesicles and exosomes, the EVs studied are considered exosome like, based on protein content. Using human glioma cell lines, the authors demonstrate that exogenous heparin sulfate can inhibit exosome uptake, and this inhibition is dependent on dose, heparin sulfation status, and chain length. Because HSPG core proteins were observed to colocalize with exosomes and cell surface HSPG levels decreased with addition of exosomes, the authors suggest that HSPGs may act as an internalizing receptor rather than simply an attachment site. Surprisingly, enzymatic depletion of heparin sulfate chains on the exosome membrane failed to alter exosome internalization, suggesting a role for the protein core. Importantly, HSPG-mediated uptake of the exosome was associated with biologic function. Inhibition of HSPG biosynthesis resulted in decreased exosome uptake and reduced cancer cell migration and ERK1/2 (MAPK3/MAPK1) signaling activation. The HSPG dependence of exosome-like particle uptake identifies a potentially targetable pathway to inhibit exosome functional activity.Trejo CL, Green S, Marsh V, Collisson EA, Iezza G, Phillips WA, et al. Mutationally activated PIK3CAH1047R cooperates with BRAFV600E to promote lung cancer progression. Cancer Res 2013;73:6448–61.Oncogenic RAS mutations are common in non–small cell lung carcinoma (NSCLC). Because oncogenic RAS is essentially undruggable, Trejo and colleagues targeted specific RAS effector pathways as an alternate strategy to model NSCLC in mice genetically engineered to express RAS effectors. Although oncogenic BRAF was sufficient for benign lung tumors, it was unable to drive malignant progression. In contrast, combined activation of BRAF and phosphoinositide 3-kinase (PI3K) led to malignant NSCLC. Monotherapy with BRAF inhibitors, but not PI3K inhibitors, effectively reduced early tumor formation. However, when mice exhibiting advanced NSCLC were treated with a combination of both inhibitors, a dramatic reduction in tumor burden and increased survival were observed. Further, whereas cells treated with a BRAF or PI3K inhibitor were cytostatic, tumor cells underwent apoptosis when treated with both inhibitors. These results suggest that PI3K signaling is not involved in the initiation of lung tumors, but rather is involved in the rate of growth and conversion of benign tumors to a malignant phenotype. These studies also suggest that targeted therapy against two RAS effector nodes is a clinically viable strategy to treat oncogenic RAS driven lung cancer.Metcalfe C, Alicke B, Crow A, Lamoureux M, Dijkgraaf GJP, Peale F. PTEN loss mitigates the response of medulloblastoma to Hedgehog pathway inhibition. Cancer Res 2013;23:7034–42.Medulloblastoma, the most common malignant pediatric brain tumor, can be divided into four distinct groups, including one dependent on Hedgehog (HH) signaling. The recent FDA approval of the HH inhibitor vismodegib for treatment of basal cell carcinoma raised an interest in this targeted therapy for HH-dependent medulloblastoma. Resistance to vismodegib occurs through attenuation of drug binding to its target and through increased PI3K activity. Metcalfe and colleagues tested the hypothesis that loss of PTEN (a negative regulator of PI3K) marks poor responsiveness to vismodegib in medulloblastoma. Using mouse models of HH medulloblastoma with or without Pten loss, they demonstrated that tumors lacking Pten were more aggressive, and that mice carrying such tumors had decreased median survival. HH-dependent, PTEN-negative medulloblastomas were also less sensitive to vismodegib than were PTEN-proficient tumors. Further, mice harboring HH-dependent Pten-negative tumors showed significant improvement when treated with both vismodegib and a PI3K inhibitor in combination. These results suggest PTEN as a biomarker for response to vismodegib in HH-dependent medulloblastoma.He WA, Berardi E, Cardillo VM, Acharyya S, Aulino P, Thomas-Ahner J, et al. NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia. J Clin Invest 2013 Oct 1[Epub ahead of print].Cachexia is a wasting condition found in several chronic illnesses. In cancer patients, especially those with pancreatic or gastrointestinal malignancies, this extreme skeletal muscle wasting represents a substantial contributor to morbidity and mortality. Using a range of experiments in mouse cancer models and patient muscle biopsies, He and colleagues studied the role of the muscle microenvironment in cachexia. They found that cachexia activated a myogenic program in muscle progenitor cells. However, these progenitor cells did not completely differentiate because they persistently expressed the unique self-renewing factor PAX7. PAX7 was induced by serum factors from cachectic mice and patients in a manner dependent on NF-κB, although the serum factor(s) responsible were not identified. Although inflammatory cytokines such as IL-6 and TNF (once named cachectin) did not recapitulate this activity, the authors nevertheless suggest that drugs targeting PAX7 or NF-κB may stimulate differentiation of myogenic cells and hence inhibit muscle loss.Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27mutant pediatric high-grade gliomas. Cancer Cell 2013;24:660–72.Pediatric diffuse intrinsic pontine gliomas show frequent gain-of-function mutation in the histone variant H3.3 (H3F3A), specifically at K27M. H3K27M leads to loss of the repression histone mark or trimethylation at K27 (loss of H3K27me3), which normally utilizes the H3K27-specific histone methyltransferase Enhancer of Zeste 2 (EZH2) within the Polycomb Repressive Complex 2 (PRC2). Bender and colleagues first showed a global loss of H3K27me3 in K27 H3.3-mutant human tumors, suggesting a dominant effect, as the mutation is not present in additional histone H3 variants. By comparison, H3.3 wild-type and histone H3 G34-mutant cortical pediatric glioblastoma tumors were shown by immunohistochemistry to be strongly positive for H3K27me3. The histone markers H3K4me3, H3K9me3, and H3K36me3 were unaffected by H3.3 K27 mutational status. Wild-type, K27M, or G34R mutant H3.3 cDNAs were expressed in glioma cells to determine their effects on histone methylation. After 25 cell passages in culture, H3K27me3 levels were significantly reduced in glioma cells expressing the K27M mutant, indicating a dominant-negative effect. The authors then showed that the K27M mutant H3.3 bound to PRC2 and inhibited its enzymatic activity. ChIP-Seq analysis of tumors harboring the K27M mutation showed a reduction of peaks associated with gene promoters and an increase in peaks associated with intergenic regions. Gene expression analysis showed a corresponding upregulation of genes correlated with loss of H3K27me3 in mutant tumors, including PDGFRA. Whole-genome bisulfite sequencing showed global DNA methylation profile changes as a result of the H3.3 K27M mutation. In addition, loss of DNA methylation was observed in the transcription start sites of genes overexpressed in the mutant tumors. Taken together, these findings show a dominant-negative K27M-induced reduction of the repressive histone mark H3K27me3 as well as global DNA hypomethylation. These two epigenetic changes activate gene expression, providing key mechanistic insights for approximately 50% of high-grade gliomas in children.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.